In overdose, the symptoms of nausea, vomiting and diarrhoea can occur. Ceftriaxone concentrations cannot be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdose should be symptomatic.
Based on literature reports, ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole and aminoglycosides.
In particular diluents containing calcium, (e.g. Ringer's solution, Hartmann's solution) should not be used to reconstitute ceftriaxone vials or bottles or to further dilute a reconstituted vial or bottle for intravenous administration because a precipitate can form. Ceftriaxone must not be mixed or administered simultaneously with calcium containing solutions including total parenteral nutrition.If treatment with a combination of another antibiotic with Megion is intended, administration should not occur in the same syringe or in the same infusion solution.
The most frequently reported adverse reactions for ceftriaxone are eosinophilia, leucopenia, thrombocytopenia, diarrhoea, rash, and hepatic enzymes increased.
Data to determine the frequency of ceftriaxone ADRs was derived from clinical trials.
The following convention has been used for the classification of frequency:
Very common (> 1/10)
Common (> 1/100 - < 1/10)
Uncommon (> 1/1000 - < 1/100)
Rare (> 1/10000 - < 1/1000)
Not known (cannot be estimated from the available data)
| System Organ Class | Common | Uncommon | Rare | Not Known a |
| Infections and infestations | Genital fungal infection | Pseudo-membranous colitisb | Superinfectionb | |
| Blood and lymphatic system disorders | Eosinophilia Leucopenia Thrombocytopenia | Granulocytopenia Anaemia Coagulopathy | Haemolytic anaemiab Agranulocytosis | |
| Immune system disorders | Anaphylactic shock Anaphylactic reaction Anaphylactoid reaction Hypersensitivityb | |||
| Nervous system disorders | Headache Dizziness | Convulsion | ||
| Ear and labyrinth disorders | Vertigo | |||
| Respiratory, thoracic and mediastinal disorders | Bronchospasm | |||
| Gastrointestinal disorders | Diarrhoeab Loose stools | Nausea Vomiting | Pancreatitisb Stomatitis Glossitis | |
| Hepatobiliary disorders | Hepatic enzyme increased | Gall bladder precipitationb Kernicterus | ||
| Skin and subcutaneous tissue disorders | Rash | Pruritus | Urticaria | Stevens Johnson Syndromeb Toxic epidermal necrolysisb Erythema multiforme Acute generalised exanthematous pustulosis |
| Renal and urinary disorders | Haematuria Glycosuria | Oliguria Renal precipitation (reversible) | ||
| General disorders and administration site conditions | Phlebitis Injection site pain Pyrexia | Oedema Chills | ||
| Investigations | Blood creatinine increased | Coombs test false positiveb Galactosaemia test false positiveb Non enzymatic methods for glucose determination false positiveb |
a Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.
Description of selected adverse reactions
Infections and infestations
Reports of diarrhoea following the use of ceftriaxone may be associated with Clostridium difficile. Appropriate fluid and electrolyte management should be instituted.
Ceftriaxone-calcium salt precipitation
Rarely, severe, and in some cases, fatal, adverse reactions have been reported in pre-term and full-term neonates (aged < 28 days) who had been treated with intravenous ceftriaxone and calcium. Precipitations of ceftriaxone-calcium salt have been observed in lung and kidneys post-mortem. The high risk of precipitation in neonates is a result of their low blood volume and the longer half-life of ceftriaxone compared with adults.
Cases of ceftriaxone precipitation in the urinary tract have been reported, mostly in children treated with high doses (e.g. > 80 mg/kg/day or total doses exceeding 10 grams) and who have other risk factors (e.g. dehydration, confinement to bed). This event may be asymptomatic or symptomatic, and may lead to ureteric obstruction and postrenal acute renal failure, but is usually reversible upon discontinuation of ceftriaxone.
Precipitation of ceftriaxone calcium salt in the gallbladder has been observed, primarily in patients treated with doses higher than the recommended standard dose. In children, prospective studies have shown a variable incidence of precipitation with intravenous application - above 30 % in some studies. The incidence appears to be lower with slow infusion (20 - 30 minutes). This effect is usually asymptomatic, but the precipitations have been accompanied by clinical symptoms such as pain, nausea and vomiting in rare cases. Symptomatic treatment is recommended in these cases. Precipitation is usually reversible upon discontinuation of ceftriaxone.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
There is evidence from animal studies that high doses of ceftriaxone calcium salt led to formation of concrements and precipitates in the gallbladder of dogs and monkeys, which proved to be reversible. Animal studies produced no evidence of toxicity to reproduction and genotoxicity. Carcinogenicity studies on ceftriaxone were not conducted.
Pharmacotherapeutic group: Antibacterials for systemic use, Third-generation cephalosporins, ATC code: J01DD04.
Mode of action
Ceftriaxone inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.
Resistance
Bacterial resistance to ceftriaxone may be due to one or more of the following mechanisms:
- hydrolysis by beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), carbapenemases and Amp C enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species.
- reduced affinity of penicillin-binding proteins for ceftriaxone.
- outer membrane impermeability in Gram-negative organisms.
- bacterial efflux pumps.
Susceptibility testing breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:
| Pathogen | Dilution Test (MIC, mg/L) | |
| Susceptible | Resistant | |
| Enterobacteriaceae | ≤ 1 | > 2 |
| Staphylococcus spp. | a. | a. |
| Streptococcus spp. (Groups A, B, C and G) | b. | b. |
| Streptococcus pneumoniae | ≤ 0.5c. | > 2 |
| Viridans group Streptococci | ≤0.5 | >0.5 |
| Haemophilus influenzae | ≤ 0.12c. | > 0.12 |
| Moraxella catarrhalis | ≤ 1 | > 2 |
| Neisseria gonorrhoeae | ≤ 0.12 | > 0.12 |
| Neisseria meningitidis | ≤ 0.12 c. | > 0.12 |
| Non-species related | ≤ 1d. | > 2 |
a. Susceptibility inferred from cefoxitin susceptibility.
b. Susceptibility inferred from penicillin susceptibility.
c. Isolates with a ceftriaxone MIC above the susceptible breakpoint are rare and, if found, should be re-tested and, if confirmed, should be sent to a reference laboratory.
d. Breakpoints apply to a daily intravenous dose of 1 g x 1 and a high dose of at least 2 g x 1.
Clinical efficacy against specific pathogens
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of ceftriaxone in at least some types of infections is questionable.
| Commonly susceptible species |
| Gram-positive aerobes Staphylococcus aureus (methicillin-susceptible)£ Staphylococci coagulase-negative (methicillin-susceptible)£ Streptococcus pyogenes (Group A) Streptococcus agalactiae (Group B) Streptococcus pneumoniae Viridans Group Streptococci Gram-negative aerobes Borrelia burgdorferi Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis Neisseria gonorrhoea Neisseria meningitidis Proteus mirabilis Providencia spp. Treponema pallidum |
| Species for which acquired resistance may be a problem |
| Gram-positive aerobes Staphylococcus epidermidis+ Staphylococcus haemolyticus+ Staphylococcus hominis+ Gram-negative aerobes Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli% Klebsiella pneumoniae% Klebsiella oxytoca% Morganella morganii Proteus vulgaris Serratia marcescens Anaerobes Bacteroides spp. Fusobacterium spp. Peptostreptococcus spp. Clostridium perfringens |
| Inherently resistant organisms |
| Gram-positive aerobes Enterococcus spp. Listeria monocytogenes Gram-negative aerobes Acinetobacter baumannii Pseudomonas aeruginosa Stenotrophomonas maltophilia Anaerobes Clostridium difficile Others: Chlamydia spp. Chlamydophila spp. Mycoplasma spp. Legionella spp. Ureaplasma urealyticum |
£ All methicillin-resistant staphylococci are resistant to ceftriaxone.
+ Resistance rates >50% in at least one region
% ESBL producing strains are always resistant
Absorption
Intramuscular administration
Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 g is about 81 mg/l and is reached in 2 - 3 hours after administration.
The area under the plasma concentration-time curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.
Intravenous administration
After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively.
Distribution
The volume of distribution of ceftriaxone is 7 - 12 l. Concentrations well above the minimal inhibitory concentrations of most relevant pathogens are detectable in tissue including lung, heart, biliary tract/liver, tonsil, middle ear and nasal mucosa, bone, and in cerebrospinal, pleural, prostatic and synovial fluids. An 8 - 15 % increase in mean peak plasma concentration (Cmax) is seen on repeated administration; steady state is reached in most cases within 48 - 72 hours depending on the route of administration.
Penetration into particular tissues
Ceftriaxone penetrates the meninges. Penetration is greatest when the meninges are inflamed. Mean peak ceftriaxone concentrations in CSF in patients with bacterial meningitis are reported to be up to 25 % of plasma levels compared to 2 % of plasma levels in patients with uninflamed meninges. Peak ceftriaxone concentrations in CSF are reached approximately 4-6 hours after intravenous injection. Ceftriaxone crosses the placental barrier and is excreted in the breast milk at low concentrations.
Protein binding
Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at plasma concentrations below 100 mg/l. Binding is saturable and the bound portion decreases with rising concentration (up to 85 % at a plasma concentration of 300 mg/l).
Biotransformation
Ceftriaxone is not metabolised systemically; but is converted to inactive metabolites by the gut flora.
Elimination
Plasma clearance of total ceftriaxone (bound and unbound) is 10 - 22 ml/min. Renal clearance is 5 - 12 ml/min. 50 - 60 % of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40 - 50 % is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.
Patients with renal or hepatic impairment
In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered with the half-life slightly increased (less than two fold), even in patients with severely impaired renal function.
The relatively modest increase in half-life in renal impairment is explained by a compensatory increase in non-renal clearance, resulting from a decrease in protein binding and corresponding increase in non-renal clearance of total ceftriaxone.
In patients with hepatic impairment, the elimination half-life of ceftriaxone is not increased, due to a compensatory increase in renal clearance. This is also due to an increase in plasma free fraction of ceftriaxone contributing to the observed paradoxical increase in total drug clearance, with an increase in volume of distribution paralleling that of total clearance.
Older people
In older people aged over 75 years the average elimination half-life is usually two to three times that of young adults.
Paediatric population
The half-life of ceftriaxone is prolonged in neonates. From birth to 14 days of age, the levels of free ceftriaxone may be further increased by factors such as reduced glomerular filtration and altered protein binding. During childhood, the half-life is lower than in neonates or adults.
The plasma clearance and volume of distribution of total ceftriaxone are greater in neonates, infants and children than in adults.
Linearity/non-linearity
The pharmacokinetics of ceftriaxone are non-linear and all basic pharmacokinetic parameters, except the elimination half-life, are dose dependent if based on total drug concentrations, increasing less than proportionally with dose. Non-linearity is due to saturation of plasma protein binding and is therefore observed for total plasma ceftriaxone but not for free (unbound) ceftriaxone.
Pharmacokinetic/pharmacodynamic relationship
As with other beta-lactams, the pharmacokinetic-pharmacodynamic index demonstrating the best correlation with in vivo efficacy is the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of ceftriaxone for individual target species (i.e. %T > MIC).
Concentrations for the intravenous injection: 100 mg/ml,
Concentrations for the intravenous infusion: 50 mg/ml
Preparation of solutions for injection and infusion
The use of freshly prepared solutions is recommended.
Megion should not be mixed in the same syringe with any drug other than 1% Lidocaine Hydrochloride solution (for intramuscular injection only).
The infusion line should be flushed after each administration.
Megion 2 g powder for solution for injection or infusion
For IV infusion 2 g Megion is dissolved in 40 ml of one of the following calcium-free infusion fluids: sodium chloride 0.9%, sodium chloride 0.45% + dextrose 2.5%, dextrose 5%, dextrose 10%, dextran 6% in dextrose 5%, hydroxyethly-starch 6 - 10%, water for injections.
The displacement volume of 2 g of Megion is 1.37 ml in water for injections. When adding 40 ml of water for injections, the final concentration of the reconstituted solution is 48.34 mg/ml.
In neonates, intravenous doses should be given over 60 minutes to reduce the potential risk of bilirubin encephalopathy.
Megion 1 g powder for solution for injection or infusion
For IV injection 1 g Megion is dissolved in 10 ml of water for injections. The injection should be administered over 5 minutes, directly into the vein or via the tubing of an intravenous infusion.
For IM injection 1 g Megion is dissolved in 3.5 ml of 1% Lidocaine Hydrochloride solution. The solution should be administered by deep intramuscular injection. Dosages greater than 1 g should be divided and injected at more than one site.
The displacement volume of 1 g of Megion is 0.71 ml in water for injections and 1% lidocaine hydrochloride solution. When adding 10 ml of water for injections, the final concentration of the reconstituted solution is 93.37 mg/ml. When adding 3.5 ml of 1% lidocaine hydrochloride solution, the final concentration of the reconstituted solution is 237.53 mg/ml.
Megion 250 mg powder for solution for injection
For IV injection 250 mg Megion is dissolved in 2.5 ml of water for injections. The injection should be administered over 5 minutes, directly into the vein or via the tubing of an intravenous infusion.
For IM injection 250 mg Megion is dissolved in 2 ml of 1% lidocaine hydrochloride solution. The solution should be administered by deep intramuscular injection. Dosages greater than 1 g should be divided and injected at more than one site.
The displacement volume of 250 mg of Megion is 0.18 ml in water for injections and 1% lidocaine hydrochloride solution. When adding 2.5 ml of water for injections, the final concentration of the reconstituted solution is 93.28 mg/ml. When adding 2 ml of 1% lidocaine hydrochloride solution, the final concentration of the reconstituted solution is 114.68 mg/ml.
Any unused product or waste material should be disposed of in accordance with local requirements.
